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Docking of molecules identified in bioactive medicinal plants extracts into the p50 NF-kappaB transcription factor: correlation with inhibition of NF-kappaB/DNA interactions and inhibitory effects on IL-8 gene expression.

Piccagli L, Fabbri E, Borgatti M, Bezzerri V, Mancini I, Nicolis E, Dechecchi MC, Lampronti I, Cabrini G, Gambari R - BMC Struct. Biol. (2008)

Bottom Line: Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score.The results obtained sustain the concept that the docking performance is predictive of a biochemical activity.In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: BioPharmaNet, ER-GenTech, Department of Biochemistry and Molecular Biology, University of Ferrara, Italy. pcclra@unife.it

ABSTRACT

Background: The transcription factor NF-kappaB is a very interesting target molecule for the design on anti-tumor, anti-inflammatory and pro-apoptotic drugs. However, the application of the widely-used molecular docking computational method for the virtual screening of chemical libraries on NF-kappaB is not yet reported in literature. Docking studies on a dataset of 27 molecules from extracts of two different medicinal plants to NF-kappaB-p50 were performed with the purpose of developing a docking protocol fit for the target under study.

Results: We enhanced the simple docking procedure by means of a sort of combined target- and ligand-based drug design approach. Advantages of this combination strategy, based on a similarity parameter for the identification of weak binding chemical entities, are illustrated in this work with the discovery of a new lead compound for NF-kappaB. Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score. All experimental analysis were in fairly good agreement with molecular modeling findings.

Conclusion: The results obtained sustain the concept that the docking performance is predictive of a biochemical activity. In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.

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Superimposition of the docked poses of inhibitors 9i, 10i and compound 21. A. the DNA binding site of NF-kappaB p50 (monomer chain A) is highlighted in green; B. the ligand atoms involved in hydrogen bonding are labeled. Compounds 9i, (shown in purple), 10i (shown in blue) and 21 are illustrated in stick representations.
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Figure 4: Superimposition of the docked poses of inhibitors 9i, 10i and compound 21. A. the DNA binding site of NF-kappaB p50 (monomer chain A) is highlighted in green; B. the ligand atoms involved in hydrogen bonding are labeled. Compounds 9i, (shown in purple), 10i (shown in blue) and 21 are illustrated in stick representations.

Mentions: Docked compounds 1–27, 9i and 10i, occupied a region of the binding surface creates by the spatial relationship between the N-terminal domain of p50 subunit and the 10 residues long linker loop (Figure 3). Molecules 21, 9i and 10i (Figure 4) were located in a small cleft surrounded by several polar amino acids (i.e. Tyr57, His109, His141, Tyr143 Lys144, Lys145, Ser208, Asp239, Lys241 and Ser208) and the highest score poses were superimposable with minimum RMSD of 1.36 Å for compounds 9i and 21. The RMSD was calculated by superimposing the following atoms pairs: heteroatoms involved in hydrogen bonding with the same residues of the protein (9i.O8 and 21.O2'; 9i.O7 and 21.O1a) (Figure 4B) and the centroid of aromatic system of coumarin structure with the centroid of benzene ring of 21. These compounds showed slightly different binding modes in p50 (chain A), p50 (chain B) and p50-p50 targets. Here we reported the highest score poses obtained from docking protocol including the similarity function. H-bond interactions between OH groups of coumarin structures (OH of benzene ring in 21) and both NH of His141 and the carboxylic group of Asp239 showed to be important for ligands binding.


Docking of molecules identified in bioactive medicinal plants extracts into the p50 NF-kappaB transcription factor: correlation with inhibition of NF-kappaB/DNA interactions and inhibitory effects on IL-8 gene expression.

Piccagli L, Fabbri E, Borgatti M, Bezzerri V, Mancini I, Nicolis E, Dechecchi MC, Lampronti I, Cabrini G, Gambari R - BMC Struct. Biol. (2008)

Superimposition of the docked poses of inhibitors 9i, 10i and compound 21. A. the DNA binding site of NF-kappaB p50 (monomer chain A) is highlighted in green; B. the ligand atoms involved in hydrogen bonding are labeled. Compounds 9i, (shown in purple), 10i (shown in blue) and 21 are illustrated in stick representations.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2543017&req=5

Figure 4: Superimposition of the docked poses of inhibitors 9i, 10i and compound 21. A. the DNA binding site of NF-kappaB p50 (monomer chain A) is highlighted in green; B. the ligand atoms involved in hydrogen bonding are labeled. Compounds 9i, (shown in purple), 10i (shown in blue) and 21 are illustrated in stick representations.
Mentions: Docked compounds 1–27, 9i and 10i, occupied a region of the binding surface creates by the spatial relationship between the N-terminal domain of p50 subunit and the 10 residues long linker loop (Figure 3). Molecules 21, 9i and 10i (Figure 4) were located in a small cleft surrounded by several polar amino acids (i.e. Tyr57, His109, His141, Tyr143 Lys144, Lys145, Ser208, Asp239, Lys241 and Ser208) and the highest score poses were superimposable with minimum RMSD of 1.36 Å for compounds 9i and 21. The RMSD was calculated by superimposing the following atoms pairs: heteroatoms involved in hydrogen bonding with the same residues of the protein (9i.O8 and 21.O2'; 9i.O7 and 21.O1a) (Figure 4B) and the centroid of aromatic system of coumarin structure with the centroid of benzene ring of 21. These compounds showed slightly different binding modes in p50 (chain A), p50 (chain B) and p50-p50 targets. Here we reported the highest score poses obtained from docking protocol including the similarity function. H-bond interactions between OH groups of coumarin structures (OH of benzene ring in 21) and both NH of His141 and the carboxylic group of Asp239 showed to be important for ligands binding.

Bottom Line: Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score.The results obtained sustain the concept that the docking performance is predictive of a biochemical activity.In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.

View Article: PubMed Central - HTML - PubMed

Affiliation: BioPharmaNet, ER-GenTech, Department of Biochemistry and Molecular Biology, University of Ferrara, Italy. pcclra@unife.it

ABSTRACT

Background: The transcription factor NF-kappaB is a very interesting target molecule for the design on anti-tumor, anti-inflammatory and pro-apoptotic drugs. However, the application of the widely-used molecular docking computational method for the virtual screening of chemical libraries on NF-kappaB is not yet reported in literature. Docking studies on a dataset of 27 molecules from extracts of two different medicinal plants to NF-kappaB-p50 were performed with the purpose of developing a docking protocol fit for the target under study.

Results: We enhanced the simple docking procedure by means of a sort of combined target- and ligand-based drug design approach. Advantages of this combination strategy, based on a similarity parameter for the identification of weak binding chemical entities, are illustrated in this work with the discovery of a new lead compound for NF-kappaB. Further biochemical analyses based on EMSA were performed and biological effects were tested on the compound exhibiting the best docking score. All experimental analysis were in fairly good agreement with molecular modeling findings.

Conclusion: The results obtained sustain the concept that the docking performance is predictive of a biochemical activity. In this respect, this paper represents the first example of successfully individuation through molecular docking simulations of a promising lead compound for the inhibition of NF-kappaB-p50 biological activity and modulation of the expression of the NF-kB regulated IL8 gene.

Show MeSH